The phospho-landscape of the survival of motoneuron protein (SMN) protein: relevance for spinal muscular atrophy (SMA)

Detering, Nora Tula; Schüning, Tobias; Hensel, Niko; Claus, Piet

doi:10.1007/s00018-022-04522-9

Cited by 9 publications

(4 citation statements)

References 200 publications

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“…However, it remains unclear how and whether phosphorylation or another type of post-translational modification could be linked to disease. For SMN protein it has been shown that half of the potential phosphorylatable residues are phosphorylated sites, and only 10 % of these sites have been found mutated in SMA patients [61] . Previous studies identified Gemin5 within the phosphoproteome regulated by RPS6KB1 [62] , a serine-threonine kinase that responds to the mammalian target of rapamycin (mTOR) signaling and promotes protein synthesis, cell growth, and cell proliferation.…”

Section: Resultsmentioning

confidence: 99%

Phosphorylation of T897 in the dimerization domain of Gemin5 modulates protein interactions and translation regulation

Francisco‐Velilla

Embarc-Buh²,

Abellan³

et al. 2022

Computational and Structural Biotechnology Journal

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Section: Resultsmentioning

confidence: 99%

Phosphorylation of T897 in the dimerization domain of Gemin5 modulates protein interactions and translation regulation

Francisco‐Velilla

Embarc-Buh²,

Abellan³

et al. 2022

Computational and Structural Biotechnology Journal

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“…[ 19 ] Homozygous mutations in SMN1 cause spinal muscular atrophy (SMA) and are regulated by SMN2 copy number, but in a minority of cases, SMA is caused by point mutations in SMN1 rather than by homozygous deletion. [ 4 , 20 , 21 ] A study found that duplication or deletion mutations in the SMN1 gene encoding the SMN protein among ALS patients lead to the skipping of exon 7 during the splicing of SMN2 pre-mRNA, resulting in a truncated mRNA that is translated into a very unstable protein (SMNΔ7), and that the loss of SMN protein function plays an important role in ALS, SMA, and other motor neuron diseases. [ 22 ] Other studies have shown that abnormal SMN1 copy number is significantly associated with genetic susceptibility to ALS and that ALS patients with no SMN1 gene expression have longer survival, [ 4 , 23 ] which is consistent with the relatively better prognosis of FAS.…”

Section: Discussionmentioning

confidence: 99%

Flail arm syndrome due to duplication mutations in the SMN1 gene: A case report

Luo

Liu

2023

Medicine

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Rationale: Flail arm syndrome (FAS) only involves the upper limbs early stage and manifests as proximal weakness and atrophy of both upper limbs and decreased tendon reflexes. As a benign variant type of amyotrophic lateral sclerosis, FAS progresses slowly, with no lower motor neuron signs in the lower limbs or bulbar muscles within 12 months after onset. Patient concerns: A 49-year-old male patient was admitted to the hospital with a 15-month history of proximal weakness and muscle atrophy in both upper limbs. His other symptoms and signs were not obvious. Diagnoses: Gene test results indicated that there were duplication mutations in the exon 7 to 8 region of the SMN1 gene. Lessons: The abnormal duplication of exons 7 and 8 of the SMN1 gene in this patient may increase the risk of FAS. Further studies are needed to identify the dominant genes and genetic factors causing males to be susceptible to FAS.

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“…Phosphorylation is one of the first modification type identified in SMN (La Bella et al, 2004). Out of the 50 putative phosphorylation sites present in SMN, 26 of them have been identified by mass spectrometry (Husedzinovic et al, 2014;Detering et al, 2022; Table 1). The phosphorylation sites span across the entire protein, with a mild enrichment in the N-terminus (Figure 1).…”

Section: Phosphorylationmentioning

confidence: 99%

“…It is plausible that amino acid changes at posttranslationally-modified sites can have a direct contribution to SMA pathogenesis. In this context, a total of 12 patient mutations have been identified in confirmed or putative phospho-sites, however their impact on the SMA phenotypes has not been determined (Detering et al, 2022). Therefore, a deeper understanding of the role of PTMs in SMN biology will be important to fully dissect the multifaceted functions of SMN and their link to SMA pathology and ultimately broaden the knowledge necessary for the development of increasingly effective therapies for SMA.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

SMN post-translational modifications in spinal muscular atrophy

Riboldi

Faravelli²,

Rinchetti³

et al. 2023

Front. Cell. Neurosci.

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Since its first identification as the gene responsible for spinal muscular atrophy (SMA), the range of survival motor neuron (SMN) protein functions has increasingly expanded. This multimeric complex plays a crucial role in a variety of RNA processing pathways. While its most characterized function is in the biogenesis of ribonucleoproteins, several studies have highlighted the SMN complex as an important contributor to mRNA trafficking and translation, axonal transport, endocytosis, and mitochondria metabolism. All these multiple functions need to be selectively and finely modulated to maintain cellular homeostasis. SMN has distinct functional domains that play a crucial role in complex stability, function, and subcellular distribution. Many different processes were reported as modulators of the SMN complex activities, although their contribution to SMN biology still needs to be elucidated. Recent evidence has identified post-translational modifications (PTMs) as a way to regulate the pleiotropic functions of the SMN complex. These modifications include phosphorylation, methylation, ubiquitination, acetylation, sumoylation, and many other types. PTMs can broaden the range of protein functions by binding chemical moieties to specific amino acids, thus modulating several cellular processes. Here, we provide an overview of the main PTMs involved in the regulation of the SMN complex with a major focus on the functions that have been linked to SMA pathogenesis.

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The phospho-landscape of the survival of motoneuron protein (SMN) protein: relevance for spinal muscular atrophy (SMA)

Cited by 9 publications

References 200 publications

Phosphorylation of T897 in the dimerization domain of Gemin5 modulates protein interactions and translation regulation

Phosphorylation of T897 in the dimerization domain of Gemin5 modulates protein interactions and translation regulation

Flail arm syndrome due to duplication mutations in the SMN1 gene: A case report

SMN post-translational modifications in spinal muscular atrophy

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